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The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases.

ABSTRACT: A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is when some viruses become reactive with PCs that they may develop high pathogenicity. Besides reacting with furin, some viruses may also react with the PCs of the other specificity group constituted by PC4/PC5/PACE4/PC7. The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses. A wide variety of PC inhibitors have been developed and tested for their antiviral activity in cell-based assays.

SUBMITTER: Izaguirre G

PROVIDER: S-EPMC6784293 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases.

Izaguirre Gonzalo G

Viruses 20190909 9

A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is ...[more]

PMID: 31505793

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Project description:Proprotein convertases (PCs), also known as eukaryotic subtilases, are a group of serine proteases comprising furin (PACE), PC1 (PC3), PC2, PC4, PACE4, PC5 (PC6), and PC7 (LPC, PC8) that generate bioactive proteins and peptides, such as hormones, receptors, and growth factors by cleaving precursor proteins at multibasic motifs. Two other family members, SKI-1/S1P and PCSK9, cleave regulator proteins involved in cholesterol and fatty acid homeostasis at nonbasic peptide bonds. Furin is ubiquitous in eukaryotic tissues and cells. PACE4, PC5, and PC7 are also widespread, whereas the expression of the other PCs is more restricted. PCs are synthesized as multi-segmented zymogens which are autocatalytically activated. The prodomains have regulatory and inhibitory functions. The catalytic domains are the most conserved domains among the PCs. The architecture of the catalytic active furin domain is known in different binding states. The C-terminal parts of the PCs differ in length and structure and contain encoded peptide signatures guiding the PCs to the subcellular destinations on the secretory pathways: SKI-1/S1P to the cis-Golgi, furin, PC5B, and PC7 to the TGN region but also to the plasma membrane. PACE4, PC5A, and PCSK9 are attached at the cell surface. Truncated, soluble furin and SKI-1/S1P, as well as PC1 and PC2, are released into the extracellular matrix. Many enveloped viruses are activated by furin and furin-like PCs and arenaviruses and a few bunyaviruses by SKI-1/S1P. The PCs cleave the viral fusion glycoprotein to trigger fusion of viral envelopes with cellular membranes to deliver the viral genome into host cells. Cleavage by PCs, occasionally in concert with other endoproteases, enables conformational changes in the viral membrane proteins needed for correct oligomerization of glycoprotein spikes and their effective incorporation into virions. Mutational alterations of PC cleavage sites can reduce the fusion potential of viral surface proteins and thus facilitate the development of secure live attenuated vaccines. Alternatively, agents preventing cleavage of viral surface (glyco)proteins block fusion capacity and multicyclic virus replications. PC inhibitors are suggested as promising antiviral drugs for quite a number of viruses causing severe infections.

Dataset Information

The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases.

Publications

The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases.

Similar Datasets

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